Hereditary Non-polyposis Colorectal Cancer (HNPCC)

Contents

Colorectal cancer is the third most common form of cancer in the United States, with approximately 130,000 cases diagnosed each year. It is also the second leading cause of cancer deaths in the United States. However, when discovered early, the disease is 90 percent curable.

Abnormalities in some of the genes in colon cells that control cell growth and death can cause colorectal cancer. Hereditary Non-polyposis Colorectal Cancer (HNPCC), which affects nearly 5 percent of colorectal cancer patients, is characterized by a mutation in an important gene, which is inherited -- or passed from parent to child.

In HNPCC, the “H” stands for hereditary, meaning it is inherited or can be passed from parent to child. “NP” stands for non-polyposis, which distinguishes HNPCC from a syndrome characterized by the formation of polyps. The “CC” stands for colorectal cancer, the most frequent cancer that develops in HNPCC families.

How is HNPCC inherited?

HNPCC is caused by an inherited mutation or abnormality in a gene that normally repairs our body's DNA. There are at least five of these genes known as mismatch repair genes that are known to be associated with HNPCC. If genetic damage is not repaired, cancer can occur. When an individual has an inherited gene mutation, it is present in the cells of all organs of the body. This makes it easier for other cancers to develop, such as cancer of the uterus or ovaries, gastrointestinal tract (stomach, small intestine and pancreas), urinary tract or kidneys.

HNPCC and cancer risk by age 70

Cancers associated with HNPCC

Lifetime risk of cancer in HNPCC

Risk in general population

Colorectal

80%

2%

Endometrial (uterine)

60%

1.5%

Ovarian

12%

1%

Stomach

13%

Less than 1%

Other cancers

1-4%

Less than 1%

Although the risk of developing cancer for people with HNPCC is high, becoming more informed about the syndrome, getting the recommended screenings and check ups, and receiving treatment by experts can help prevent cancer and save lives.

How is HNPCC diagnosed?

Family History

A detailed family history is the first step in determining if your family may be affected with HNPCC or an inherited colon cancer syndrome. There are several criteria that alert your healthcare provider to a possible diagnosis of HNPCC.

The most strict include:

Amsterdam I:

Three relatives with colorectal cancer

One case of colorectal cancer diagnosed in a relative at or before age 50

One relative with colorectal cancer is a first-degree (parent, child, sibling) to the other two with colorectal cancer

Colorectal cancer occurs in two successive generations

Less strict criteria include:

HNPCC-Like:

Families with two colorectal cancers and one uterine cancer, or two relatives with colorectal cancer and advanced precancerous polyps

One colorectal cancer or uterine cancer diagnosed at or before age 50

One relative with cancer is a first-degree to the other two with cancer or polyps

Cancers occur in two successive generations

Amsterdam II:

Two HNPCC-associated cancers*

One relative with cancer is a first-degree to the other two with cancers

Other clues used in the diagnosis of HNPCC in a family include multiple relatives with colorectal cancer, especially at a young age, persons who have had more than one colorectal cancer, or clusters of colorectal and other HNPCC-associated cancers.

Genetic Testing

If the family history is suggestive of HNPCC, genetic counseling is recommended prior to genetic testing. A genetic counselor will review your family history and also will discuss the important issues regarding testing, including your emotional well-being.

If there is a high likelihood that your family has an inherited colon cancer syndrome, DNA sequencing (blood testing) for the gene mutations known to cause HNPCC may be recommended. Approximately 50 percent of HNPCC families have a mutation detected. If it is detected in the family, other relatives may subsequently be tested. Importantly, a positive gene test in someone only confirms that the gene mutation has been inherited; it does not detect polyps or cancer.

Microsatellite instability (MSI) is an alternative method of testing is sometimes done on cancerous tissue or polyps. A positive MSI test, along with a strong family history, is highly suggestive of HNPCC. However, genetic testing with direct DNA sequencing should follow.

In patients with a positive DNA test, regular colorectal and gynecologic surveillance is required to prevent or detect cancer in its early, curable stages. If a family chooses not to undergo genetic testing, or the mutation cannot be found, regular surveillance also is needed.

How can cancer be prevented in an HNPCC family?

In order to prevent colorectal cancer, regular colonoscopies are required. In the majority of cases, cancer develops from adenomatous polyps that can be removed during the colonoscopy.

Besides regular screening, a healthy diet and lifestyle can aid in colorectal cancer prevention. Be sure to consult with your doctor before making any lifestyle changes.

If cancer is found, surgical removal of the entire colon is the only definite way to prevent colon cancer from recurring. Following surgery, most patients are able to eat normal diets and lead normal lives.

HNPCC families can be followed in a registry, such as the David G. Jagelman Inherited Colorectal Cancer Registries at Cleveland Clinic. The main purpose is to prevent needless deaths from colon cancer by providing the best care, promoting knowledge of the risks, and conducting research.

What is recommended for screening of HNPCC patients?

Method: colonoscopy Age to Begin: At 21 years, or ten years younger than the youngest person diagnosed with colorectal cancer in the family, whichever is earlier. Interval: Every two years until age 40 and then every year thereafter

Method: Pelvic exam, transvaginal ultrasound and CA-125 (blood test for ovarian cancer) Age to Begin: 25-35 years Interval: Every year

Method: Endometrial biopsy Age to Begin: As symptoms arise, such as persistent, unusual vaginal bleeding

Method: Urine cytology This is especially important for families who have someone diagnosed with transitional cell carcinoma of the ureter or renal pelvis. Age to Begin: At 30 years Interval: Every one to two years

Other cancers that occur in the family may require specialized testing beyond these basic recommendations.